Historically, the formation of aromatic C—F bonds has been challenging in the field of synthetic organic chemistry, and even more so in radiochemistry, with the short-lived radionuclide fluorine-18 (18F; t1/2=109.7 min) for molecular imaging by positron emission tomography (PET).
Fluorine-18 labelled compounds and radiopharmaceuticals are the mainstay of functional molecular imaging by positron emission tomography (PET) for a broad range of applications including clinical diagnosis and drug discovery. Consequently, there is a rapidly growing demand for new 18F-labelled agents to probe biological processes and targets in vivo.
Fluorine-18 is most readily prepared in high specific activity as no-carrier-added [18F]fluoride ion, by proton irradiation of [18O]H2O (18O(p,n)18F nuclear reaction) in low energy (10-16 MeV) medical cyclotrons. Most 18F-labelling methodologies for aromatic nucleophilic substitution (SNAr) reactions employ naked [18F]fluoride ion with appropriately activated (electron-deficient) aromatic/heteroaromatic substrates. However, radiofluorination of non-activated arenes represents a major challenge in the field and there is an urgent need for a general and practical methodology that can introduce 18F into molecules which cannot be labelled using a conventional aromatic nucleophilic substitution (SNAr) reaction.
Electrophilic fluorination reactions with carrier-added 18F—F2 gas and its derivatives (e.g., 18F—CH3CO2F) have enabled the development of 18F-labeled aromatics by direct electrophilic substitution or demetalation reactions with organometallic reagents such as aryl stannanes (Miller et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033). Electrophilic radiosynthesis with 18F—F2 and its derivatives involve the use of carrier-added fluorine gas and consequently result in products with relatively low specific activities. Such reactions also require specialized equipment as well as technical expertise for the safe handling of F2 (g). Commercial availability of high specific activity, no-carrier added 18F-fluoride has led to this reagent becoming the most widely used radiofluorinating species. Synthesis of aromatic molecules with 18F-fluoride is typically achieved by nucleophilic aromatic substitution (SNAr) reactions with electron-deficient (activated) aromatics, and these reactions have been used extensively to prepare high specific activity radiopharmaceuticals (Cai et al., Eur. J. Org. Chem. 2008, 2853-2873). However, labeling of electron-rich (non-activated or deactivated) aromatics with 18F-fluoride remains a long-standing and unmet challenge in routine PET radiopharmaceutical production.